This invention relates generally to a nutritionally complete liquid supplement (referred to as xe2x80x9cproductxe2x80x9d) for enteral feeding, which has been formulated to address the nutritional needs of persons undergoing renal dialysis because they suffer from renal failure. The product is formulated for persons who suffer from acute or chronic inflammation of kidney tissue; in particular, those who have a dysfunctional glomerulus, which is a cluster of capillaries responsible for the production of urine.
It is well established that renal disease affects the nutritional status of a person with renal failure, both directly and indirectly in so many ways, that it is difficult to achieve a caloric goal by controlling the person""s diet. Major factors which determine the quality of life for a patient are (a) the nutritional status of the patient when dialysis was commenced; and, (b) the patient""s ability to ingest and most efficiently metabolize the nutrition provided. On the reasonable assumption that protein administration may also enhance the rate of recovery from acute renal failure, U.S. Pat. No. 5,576,287 to Zaloga et al claims a method for treating or preventing such failure by feeding the patient meat proteins but fails to teach how elemental arginine, or how much of it, can be added to improve glomerular function; or, how the calcium to phosphorus ratio can be controlled. By xe2x80x9celementalxe2x80x9d arginine is meant molecular arginine (MW=174.2) which is soluble in water. Meat proteins elevate the phosphorus level and there is no indication how the calcium content is increased relative to the phosphorus to maintain a Ca/P ratio greater than 1. Calcium is malabsorbed in patients with renal disease, and they require a relatively high dietary intake; phosphorus is poorly excreted, and due to high plasma levels, phosphorus intake must be limited. A ratio greater than 1, on an elemental basis, w/w (weight for weight), helps to optimize the Ca/P balance of a renal patient undergoing dialysis. The ""287 composition may also include any other nutrients including amino acids known to have specific renal vasodilator actions.
Numerous considerations relating to the problems of providing a diet which will determine the availability of desirable nutrients are referred to in U.S. Pat. No. 5,108,767 to Mulchandani and need not be reiterated. Health care professionals dealing with a patient undergoing dialysis must cope with the need to replace the function of the kidneys. They refer to arginine as a non-essential amino acid and do not suggest providing it in elemental form. Neither the ""287 nor the ""767 disclosures provides the requisite motivation to prepare an acceptable renal nutritional supplement with elemental L-arginine.
Choosing a renal diet is complicated because specific nutrient requirements and limitations vary from patients who have acute renal failure to those who have chronic renal failure or end-stage renal disease. The choice depends on the stage of renal disease, the type of treatment prescribed and whether the patient has diabetes (present in up to one half of all renal patients). The challenge is to balance the need to limit the intake of essential nutrients such as phosphorus, potassium and sodium with the need to provide sufficient protein and energy to maintain nutritional health.
The primary nutritional need for patients undergoing hemodialysis or peritoneal dialysis is to maintain metabolic homeostasis (normal functional indices, positive nitrogen balance, and a stable weight) by feeding them, either as a sole or supplemental source of nutrition, a balanced nutritional product, when they need a nutritionally complete product. Particularly since L-arginine, its precursors and its metabolites are deemed to be at the center of the interaction of different metabolic pathways and interorgan communication (see xe2x80x9cRole of arginine in health and in renal diseasexe2x80x9d by Reyes, Alvaro A. et al, Am. J. Physiol. 267 F331-F346 1994), and deemed particularly beneficial for glomerular function, the product is fortified with arginine, making it more available, because free amino acids having molecular weights of less than about 500 are rapidly absorbed. Other necessary elemental ingredients, e.g. minerals, vitamins and protein may be added as desired, and even additional free amino acids, as long as the following critical properties of the final product are met: pH in a slightly acidic or neutral range e.g. in the range from about 6 to about 8, osmolality below 1000 mOsm/kg water, and viscosity less than 100 cp.
Since a hemodialysis patient averages three treatments per week, or once every 56 hours, though the typical patient is not treated after equal intervals, it is essential that the level of arginine in the bloodstream be maintained. L-arginine is deemed an essential amino acid in patients with renal failure because of the role it plays in the synthesis of endothelium-derived relaxing factor, bacterial killing by macrophages, and production of polyamines (see xe2x80x9cAmino Acid Profile and Nitric Oxide Pathway in Patients on Continuous Ambulatory Peritoneal Dialysis: L-Arginine Depletion in Acute Peritonitisxe2x80x9d by Heesuk Suh, Tatyana Peresleni, et al Am. Jour. Kidney Diseases, Vol 29, No 5 (1997), pp 712-719). Arginine deficiency is suggested as a cause for several aspects of the uremic syndrome, such as impaired blood pressure control, atherogenesis, vascular smooth muscle cell proliferation, macrophage toxicity, and impaired antibacterial defense (see xe2x80x9cClinical Nutritionxe2x80x94Enteral and Tube Feedingxe2x80x9d by John L. Rombeau and Rolando H. Rolandelli, 3rd edition, pg 448). The maintenance of normal levels of L-arginine depends on the levels of dietary intake of the amino acid. Though the foregoing indicated the beneficial effect of L-arginine, in view of its well-known unpleasant taste, they offered no suggestion as to how arginine in elemental form might be included in a practical, stable liquid nutritional supplement. The problem is to formulate a product with the requisite amount of elemental arginine, yet maintain desirable viscosity and osmolality; also, to imbue it with a good taste, to find the appropriate order of incorporating the components of the recipe to yield desirable organoleptic properties, and to ensure that upon sterilization and packaging, the effectiveness of the arginine is not lost in the product which retains those desirable properties and remains shelf-stable for at least one year.
The composition of this invention is nutritionally complete, by which term is meant that the composition contains adequate nutrients to sustain healthy human life for extended periods. The composition can be cow milk-based, soy-based, or based on other proteins or nutrients, provided it is fortified with at least enough elemental arginine to double the contribution of arginine available from a chosen source of protein. The caloric density of the nutritionally complete composition of the invention contains about 2 cal/ml (calories per milliliter) in a ready-to-feed form. The liquid, nutritionally complete product flows easily under gravity, through a conventional feeding tube, and has tolerable osmolality adapted for an adult enteral composition that is intended to come into contact with the gastric contents of the stomach. Though the product is formulated to be tube-fed, it may also be administered via the normal oral route, and since the latter is preferred, the product""s good taste is an important factor. The detrimental effect of bitter elemental arginine on the taste of any formulation containing more than a trace amount had to be overcome. The good taste of the product is provided by the fortuitous effect of one or more carboxylic acids which also function to neutralize the high pH of the arginine. In each formulation, magnesium is provided in the form of magnesium carbonate, magnesium sulfate or magnesium oxide, all deemed undesirable in the ""767 formulation (col 10, lines 45-50). In a retorted product, citric acid is essential in combination with citrates of sodium, and/or potassium and/or calcium, and the ""767 patent teaches that no citric acid should be used (col 6, lines 43-44).
L-arginine, which is known to be a non-essential amino acid, is critical for enhancing the glomerular function of the kidneys; and, at least as much elemental arginine is added in a liquid formulation as is present in protein incorporated in the liquid, typically contributing at least about 0.5% of total calories, and preferably from 0.75% to 7% of total calories in the formulation. Because of the combination of a carboxylic acid with elemental arginine, the presterilized liquid formulation has a pH in the range from 6 to 8, preferably from 6.5 to 7.5; a viscosity less than 100 cp, preferably 30 to 70 cp; and an osmolality of less than about 1000 mOsm/kg water, preferably from about 500 to 900 mOsm/kg water. Unexpectedly, combining the L-arginine with one or more specific carboxylic acids not only lowers the pH into the desirable range, but also imbues the product for oral ingestion with a pleasant taste which may be enhanced by other ingredients of the nutritionally complete composition. In the xe2x80x9coralxe2x80x9d formulation, neutralizing the arginine with lactic, adipic or malic acids, which are examples of xe2x80x9carginine-neutralizing acidsxe2x80x9d, suppresses the bad taste of arginine, lowers the pH and provides a key ingredient which controls viscosity; varying the levels of staple nutrient components within allowable ranges has surprisingly little effect on the taste, but influences other properties substantially. The formulation is stabilized without the use of commonly used protein stabilizers, and is aseptically sterilized at a temperature below 300xc2x0 F. for from 3 to 10 sec. In the formulation for a retorted product, neutralizing the arginine with a combination of citric acid and citrates (which act as a buffer), in a citric/citrate ratio in the range from 2 to 8, preferably from 2.5 to 6, both lowers the pH into the desired range as well as stabilizes the protein so that it survives high temperature sterilization in the range from 250xc2x0 F. to 270xc2x0 F. for from 10 to 20 min.
This nutritional product is calorie and nutrient-dense, has moderate to high protein content, and a high calcium to phosphorus ratio of at least 1:1, preferably in the range from about 1:1 to 2:1. The product contains about 100 g fat/L, about 200 g carbohydrate/L, and essentially no sugars such as sucrose, lactose or fructose which have an inordinately high adverse effect on osmolality. If desired, a small amount of fructose, contributing less than 1.5% of total calories, may be added provided the desired osmolality of the formulation is maintained. In addition, 8 fl oz of the product which provides about 475 cal, contains from 25 mg to 75 mg of magnesium, and 1 liter meets at least 100% of the RDI (reference daily intake) for vitamins and minerals with the exception of chloride, vitamin D, vitamin A, phosphorus, magnesium, chromium and molybdenum. Yet, the product meets the nutritional requirements of a renal patient. Specifically the product is low in phosphorus content and contains L-arginine to help maintain a desirable normal level for each patient.
A specific product which provides about 2 cal/ml is characterized by having less than 80% by weight water, and the addition of enough elemental arginine to contribute from about 0.75% to 3% total calories. The balance of arginine may be derived from caseinates. The caloric distribution for such a product is as follows: from all arginine 1.2% to 3%; from protein, 12 to 18%; from fat, 40 to 46%; the balance from carbohydrates. In one preferred formulation flavored for oral use, containing essentially no sucrose, lactose or fructose, and lactic acid as taste-suppressant, for those patients who tend to absorb aluminum-containing phosphate binders which are prescribed, no citric acid or citrates are present; in another formulation for tube feeding, containing a combination of citric acid and citrates as taste-suppressant, essentially no lactose, sucrose or fructose is present. Citrates are chosen from the salts of sodium, potassium and calcium to provide a desired balance of the levels of each. Most preferably, a citric acid and citrates-containing formulation is packaged in a retortable container for tube feeding, being hermetically sealed, sterilized and shelf-stabilized at about 256xc2x0 F. for 13 min. An aseptically sterilized container is sterilized at about 280xc2x0 F. for 4.5 sec, for oral or tube feeding a product with no citric acid or citrates. In each product, changing the order of addition of the arginine relative to the protein and carbohydrates, and that of the oils relative to the foregoing, produces an undesirable product.